tbuckley/cabot-search huggingface dataset:
Abstract 1319: Saffron (<i>Crocus sativus</i>) extract inhibits migration and invasion of cancer cells through modulation of MMP-3 and MMP-9 expression
Authors: Tyler King, Stefana Moscardini, McKenzie Martin, Fatima K. Rehman
Journal: Cancer Research (2023)

Abstract Saffron is a spice that has been used throughout history for various therapeutic properties. Recently, it has also been documented to have a significant anticancer effect on primary tumors. However, limited studies are found studying its effect on the metastatic potential of cancers. The goal of our study was to explore the effect of saffron on the migration and metastatic potential of breast cancer cells. Methods: MDA468 breast carcinoma cells were treated with varying concentrations of Saffron (100-1000 ug/mL) and examined using Q-phase holographic time-lapse microscopy to measure the movement of cells over time. The anticancer activity of Saffron was confirmed using cell viability assays. Invasion and metastatic potential were studied using Boyden-chamber and scratch wound assays. Finally, the tumorigenicity of the cell line was examined through colony formation assays in the presence and absence of Saffron. Results: Q-phase microscopy revealed a reduction in projections and significantly reduced movements in cells after Saffron treatment. The inhibition of migration, cell mobility and invasion by Saffron was confirmed through scratch wound and Boyden chamber assays (p&amp;lt;.01). Saffron extract also resulted in inhibition of viability in a dose-dependent manner and colony formation assays found markedly reduced size and number of colonies in the presence of the extract. Western blot results showed marked reduction of MMP-3 and MMP-9 expression in Saffron-treated cells. Conclusions: Our results found saffron to be effective in decreasing breast cancer carcinoma cells MDA468’s viability, migration, and tumorigenicity. Initial results indicate that Saffron may reduce migratory ability of cancer cells through the modulation of metalloproteinases. Citation Format: Tyler King, Stefana Moscardini, McKenzie Martin, Fatima K. Rehman. Saffron (Crocus sativus) extract inhibits migration and invasion of cancer cells through modulation of MMP-3 and MMP-9 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1319.
Abstract 61: PRDM16 is key for promoting bone metastatic prostate cancer cell survival during entry into dormancy
Authors: Mostafa Nasr, Tao Li, Ryan T. Bishop, Conor C. Lynch
Journal: Cancer Research (2023)

Abstract Recurrent metastatic prostate cancer (PC) typically manifests in the skeleton. Despite our knowledge that DTCs give rise to incurable bone metastatic PC, the molecular mechanisms underpinning their entry into dormancy and exit, remain under-investigated. To address this, we developed a novel in vitro model of PC dormancy as determined by increased entry into G0/G1 state (flowcytometry) and increased p38/ERK activity ratio &amp; p27 (immunoblotting). Interestingly, we also observed dormancy entry resulted in the formation of clusters that remained dormant for long periods (21 days) and could be reawakened via serum addition. RNASeq and bioinformatic analysis of control vs. dormant cells revealed PRDM16 to be significantly elevated during entry into dormancy across mouse (RM1) and human cell lines (LAPC4, 22RV1). In vitro, we observed that genetic silencing of PRDM16 leads to a significant reduction in the ability of PC cells to enter dormancy. Analyses show that PRDM16 increases the expression of anti-apoptotic proteins including BCL-2 while inhibiting pro-apoptotic proteins such as BIM and NOXA. Our preliminary data shows that PRDM16 expression in CRPC cells can be induced by BMP7 and conversely decreased by the BMP signaling antagonist, noggin, factors with known critical roles in regulating bone homeostasis. In vivo, we used intrailiac-artery technique to deliver actively growing RM1 cells or dormant RM1 clusters (D-RM1) to the hind limbs (n = 8) of syngeneic mice (C57BL/6). Bioluminescence shows that D-RM1 remains dormant for more than 30 days. Subsequent histological analyses show that D-RM1 home preferentially to the endosteal niche where, compared to RM1 controls, they remain largely negative for ki-67 and cleaved caspase 3 and exhibit high expression of PRDM16. In conclusion, our data points to PRDM16 as a key regulator of survival pathways during PC entry into dormancy. Citation Format: Mostafa Nasr, Tao Li, Ryan T. Bishop, Conor C. Lynch. PRDM16 is key for promoting bone metastatic prostate cancer cell survival during entry into dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 61.
Abstract 5192: NCG-MHC-dKO mice: an excellent model for PBMC reconstitution and pharmacodynamic evaluation in the absence of GvHD
Authors: Huiyi Wang, Jun Xing, Jialu Fan, Huanhuan Hou, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju
Journal: Cancer Research (2023)

Abstract Human immune cell reconstitution (PBMC or CD34+ hematopoietic stem cell; HSC) is commonly performed in immunodeficient mouse strains such as NCG, NSG, or NOG. The use of PBMC is preferred for multiple reasons, including faster engraftment, lower cost, and the presence of mature immune cell populations. Although there are donor-to-donor variations in GvHD occurrence, and specific donors can be screened, the symptoms of GvHD typically occur within 4 weeks. GvHD significantly limits the study window required to evaluate the efficacy of therapeutic agents, such as cancer immunotherapies. GvHD is an immune reaction triggered mainly by donor T cells identifying the mouse MHC class I and class II as foreign and attacking the host cells and organs. Deletion of β2m (NCG- β2m-KO) reduces the occurrence of GvHD; however, β2m is not only in the MHC class I subunit but also in the FcRn subunit, of which deletion shortens the half-life of IgG, making it unsuitable for IgG antibody agent evaluation. In addition, the deletion of MHC class I or class II alone results in an imbalanced CD4/CD8 ratio. To solve these problems, we developed the NCG-MHC-dKO mouse model by knocking out the H2K1, H2D1, and H2Ab1 genes. Compared with the existing NCG- β2m-KO or other β2m null mouse models, the NCG-MHC-dKO significantly prolonged survival, reduced GvHD occurrence, and did not affect the CD4/CD8 ratio when reconstituted with PBMC. Furthermore, treatment with anti-PD-L1 antibodies significantly inhibited MDA-MB-231 tumor cell growth in PBMC-reconstituted NCG-MHC-dKO mice, similar to NCG mice. Based on our preliminary data, the NCG-MHC-dKO mouse is a promising model for antibody and cell therapy agent evaluation, assessing treatment-related cytokine release syndrome, and evaluating long-term toxicities of cell therapies. Citation Format: Huiyi Wang, Jun Xing, Jialu Fan, Huanhuan Hou, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju. NCG-MHC-dKO mice: an excellent model for PBMC reconstitution and pharmacodynamic evaluation in the absence of GvHD. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5192.
Abstract 3773: DeMixMir: deconvolution of microRNA sequencing data from heterogeneous tumor samples
Authors: Matthew Montierth, Kinga Nemeth, Xinghua Tao, George Calin, Wenyi Wang
Journal: Cancer Research (2023)

Abstract Measuring tumor heterogeneity is a key issue in modern clinical oncology, with relevance to understanding cancer progression, resistance to therapy, and recurrence. Studies of the transcriptomic landscape in cancer have rapidly advanced in scale, enabled by novel methods and advancing technologies. One such novel method is TmS, a computational estimate of tumor-specific total messenger RNA content from heterogeneous tumor samples, which is calculated by combining genomic and transcriptomic deconvolutions. We have previously shown TmS as a promising pan-cancer biomarker for patient prognosis. Given the fruitful study of tumor cell total messenger RNA content, a logical extension is to investigate the utility of estimating tumor cell content of other RNA species. MicroRNAs (miRNAs) are small noncoding RNAs that regulate mRNA expression, and their dysregulation is a hallmark feature observed across cancers. A computational method to derive tumor cell total miRNA content from bulk sequencing data is especially needed since miRNAs cannot yet be reliably profiled at single cell resolution. Here we develop and benchmark DeMixMir, a new expansion of our reference-free transcriptomic deconvolutional model DeMixT, in order to recover tumor-specific miRNA proportions from mixed samples. For benchmarking, we generated an artificially mixed dataset of small RNA sequencing consisting of a total of 30 samples that were made by mixing HS-5 fibroblast cells with either wildtype or Dicer1 knockout HCT116 colorectal cancer cells. The tumor and fibroblast cell lines were mixed at 5 different proportions, to simulate a broad spectrum of tumor/nontumor cell mixing scenarios, with three independent replicates generated at each mixing ratio. DeMixMir demonstrated high accuracy in estimating the tumor-specific miRNA proportions in both the wildtype and the Dicer1 knockout mixtures. We further calculated tumor cell total miRNA content using DeMixMir output. Our proof-of-concept study suggests estimating tumor cell total miRNA content across tumor tissues at scale is feasible and likely valuable for advancing understanding of the complex roles miRNAs play in the cancer ecosystem. Citation Format: Matthew Montierth, Kinga Nemeth, Xinghua Tao, George Calin, Wenyi Wang. DeMixMir: deconvolution of microRNA sequencing data from heterogeneous tumor samples. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3773.
Abstract 5722: The mutational signatures of 100,477 targeted sequenced tumors
Authors: Donghyuk Lee, Min Hua, Difei Wang, Lei Song, Tongwu Zhang, Kai Yu, Xiaohong R. Yang, Jianxin Shi, Stephen J. Chanock, Maria Teresa Landi, Bin Zhu
Journal: Cancer Research (2023)

Abstract Mutational signatures, the footprints of somatic mutations, are associated with the causes of cancer and have been well-studied for tumors with whole exome or genome sequencing. However, due to the low number of detected mutations, mutational signatures were insufficiently explored for many tumors sequenced by targeted panels in clinics. It impedes the clinical application of mutational signatures. Here, we present a new method, SALMON (Signature Analyzer for Low Mutation cOuNts), to identify mutational signatures in targeted sequenced tumors based on tumor mutational burden. SALMON adjusts for panel size differences and uses a large number of targeted sequenced tumors rather than a large number of mutations per tumor (as with whole exome or genome sequencing) to overcome the challenges of mutational signature analysis for targeted sequencing. Extensive simulations and pseudo-targeted sequenced data show that SALMON can accurately detect spiky or common signatures. We applied SALMON to investigate the pan-cancer patterns of mutational signatures for 100,477 targeted sequenced tumors in AACR Project GENIE, including 14,428 lung and 11,389 breast tumors. We detected well-established signatures in tumor types that have not previously been associated with these signatures, such as the smoking signature in ovarian tumors. Interestingly, analysis of thousands of tumors per cancer type from diverse populations revealed gender discrepancies, self-described race differences, subtype heterogeneity, and metastatic enrichment of mutational signatures. For instance, most sex-biased signatures are more frequently present in males for non-gender-specific cancers. Thiopurine treatment-induced signature in glioma is enriched in Black patients. And endometrioid ovarian or uterine cancers have a higher prevalence of polymerase epsilon (POLE) deficiency-related signatures than non-endometrioid ovarian or uterine cancers, respectively. Our study demonstrates the feasibility and utility of mutational signature analysis for targeted sequenced tumors, enabling precision applications of mutational signatures in the clinical setting. Citation Format: Donghyuk Lee, Min Hua, Difei Wang, Lei Song, Tongwu Zhang, Kai Yu, Xiaohong R. Yang, Jianxin Shi, Stephen J. Chanock, Maria Teresa Landi, Bin Zhu. The mutational signatures of 100,477 targeted sequenced tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5722.
Abstract 4919: Estrogen regulates the immune microenvironment and immunotherapy response of colorectal liver metastases
Authors: Yasmine Benslimane, Sarah Lapin, Julien Chambon, Stephanie Perrino, Pnina Brodt
Journal: Cancer Research (2023)

Abstract Liver metastases (LM) remain a major cause of cancer-related death and many cancers preferably metastasize to the liver due to its unique anatomical location, rich blood supply and immune-tolerant microenvironment. Up to 50% of colorectal carcinoma patients develop LM during their disease and this is associated with a poor prognosis. Our laboratory previously identified a sexual dimorphism in the regulation of the immune microenvironment (IME) of LM and showed that estrogen could promote the accumulation of myeloid-derived suppressor cells (MDSCs) and Tregs in the liver in response to invading cancer cells. The objective of this study was to elucidate the role of estrogen in the recruitment and polarization of other immune cells and to determine the therapeutic potential of Selective Estrogen Receptor Degrader (SERD) therapy in CRCLM bearing female mice, and evaluate if SERD would improve anti PD-1 immunotherapy efficacy. In estrogen-competent female mice bearing CRCLM, we found increased gene and protein expression of the immunosuppressive cytokine TGF-β, and inversely a decrease in the pro-inflammatory cytokine TNF-alpha. Furthermore, we identified a significant decrease of immunosuppressive CD68+CD163+ M2 macrophages, and an increase of the pro-inflammatory CD68+TNF-alpha+ M1 macrophages in estrogen-depleted (ovariectomized) mice as compared to estrogen-competent mice. This observation was reversed upon estradiol supplementation. Moreover, treatment of female mice with the SERD Fulvestrant, markedly reduced the number of CRCLM compared to vehicle-treated mice, reduced the cell frequencies and counts of M2 macrophages, significantly increased NK cells recruitment in the liver. The addition of SERD to immunotherapy has a better therapeutic effect than both therapies alone, and increased CD8+ T-cells, NK cells, and M1/M2 macrophages ratio. Taken together, our results identify estrogen as a critical regulator of an immunosuppressive TME in the liver and a potential therapeutic target to enhance immunotherapy efficacy. Citation Format: Yasmine Benslimane, Sarah Lapin, Julien Chambon, Stephanie Perrino, Pnina Brodt. Estrogen regulates the immune microenvironment and immunotherapy response of colorectal liver metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4919.
Abstract 5739: Targeting WEE1 to improve the therapy of KRAS G12C mutant non-small cell lung cancer
Authors: Gaku Yamamoto, Kosuke Tanaka, Ryo Kamata, Shunta Mori, Jie Liu, Toyohiro Yamauchi, Yuta Sakae, Akihiro Ohashi, Susumu S. Kobayashi
Journal: Cancer Research (2023)

Abstract Background: While sotorasib is the first clinically approved small-molecule inhibitor of KRAS G12C in non-small-cell lung cancer (NSCLC), efficacy of sotorasib alone is limited, presumably due to adaptive resistance mechanisms in cancer cells. To expand therapeutic potential of sotorasib, combination strategies need to be developed. In this study, we conducted a large-scale screening to identify novel combination candidates with sotorasib. In addition, molecular mechanisms of synergistic effects were investigated in multiple preclinical models. Methods: To identify novel combination partners of sotorasib, we conducted high-throughput screening using a kinase inhibitor library containing 1,400 chemical compounds. Anti-proliferative and apoptotic effects in vitro were assessed by ATP-based cell viability assay and/or clonogenic assay, and caspase 3/7 assay and/or Annexin V assay, respectively. Synergistic effects were evaluated by calculating the BLISS index and visualized by SynergyFinder Plus. Immunoblotting was performed using antibodies against pCDK1 (Tyr15), pERK, pAkt, MCL1, BIM, PUMA, BCL2, or BCL-xL. In vivo efficacy studies were performed using a KRAS G12C mutant H358 xenograft nude mouse model. Results: Through the large-scale unbiased combination screening of -1,400 kinase inhibitors, we identified a WEE1 inhibitor (AZD1775), a G2/M checkpoint abrogator in clinical-stage development, as a promising combination partner of sotorasib in KRAS G12C mutant NSCLC. The synergistic effects in vitro were broadly observed in multiple KRAS G12C mutant NSCLC cell lines, regardless of single-agent sensitivity to sotrasib or co-occurring oncogenic mutation profiles. The combination treatment upregulated pro-apoptotic protein BIM, leading to apoptosis. In vivo efficacy studies in H358-xenografted models also demonstrated remarkable tumor regression and durable response in mice treated with sotorasib and AZD1775 compared to ones with a single agent alone. Conclusion: We identify AZD1775, a WEE1 inhibitor, as a novel combination candidate, which enhanced the anti-tumor activity of sotorasib both in vitro and in vivo preclinical models. These findings can lead to a novel therapeutic strategy for KRAS G12C mutant NSCLC. Citation Format: Gaku Yamamoto, Kosuke Tanaka, Ryo Kamata, Shunta Mori, Jie Liu, Toyohiro Yamauchi, Yuta Sakae, Akihiro Ohashi, Susumu S. Kobayashi. Targeting WEE1 to improve the therapy of KRAS G12C mutant non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5739.
Abstract 1397: Collagen COL26A1 promotes papillary thyroid cancer invasion and metastasis and correlates with poor survival and clinical outcomes
Authors: Michelle Carnazza, Danielle Quaranto, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari
Journal: Cancer Research (2023)

Abstract Papillary thyroid cancer (PTC) is the most common cancer in women under 25 years of age and is increasing in incidence. While PTC is often slow-growing and surgically resectable, recurrence years to decades after initial surgery occurs in ~20% of patients (now only in their 40s/50s), with mortality of 38-69%. The identification of both prognostic biomarkers and actionable therapeutic targets for high-risk PTC at diagnosis is critically important and an unmet need. RNASeq analysis of 45 PTC and matched normal patient tissues from our biobank identified collagen 26A1 (COL26A1) as significantly upregulated in patients with higher risk extrathyroidal extension, lymph node metastasis, and multifocal tumors, compared to those with localized disease. Kaplan Meier survival curves of The Cancer Genome Atlas (TCGA) data confirmed that increased COL26A1 expression significantly decreases survival probability by 25% (p=0.0086). Further analyses of TCGA data indicated that COL26A1 expression significantly correlated with clinical attributes including MACIS score (q=0.001), differentiation score (q=0.025), and tumor stage (q=0.025). Data from our in vitro culture PTC model system indicated that COL26A1 expression was increased 3X in PTC cell line K1, compared to immortalized “normal” thyroid epithelial cells, NThy-ori-3-1. Two CRISPR guides designed to target COL26A1 introduced into K1 resulted in repression of COL26A1 RNA and protein levels by 50% and 70%, respectively. COL26A1 repression decreased critical tumor phenotypes of aggressiveness and metastasis including proliferation (30%), clonogenicity (33%), anchorage-independent growth (37%), cell motility (43%), invasion (30%) and migration (33%). Cell-to-cell adhesion and cell-matrix adhesion also decreased (36% and 25%, respectively). Thus, COL26A1 may have use as a prognostic marker and actionable target for small molecule inhibitors in PTC. Citation Format: Michelle Carnazza, Danielle Quaranto, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari. Collagen COL26A1 promotes papillary thyroid cancer invasion and metastasis and correlates with poor survival and clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1397.